Cyclopropyl‐enhanced bioavailability, not target‐site potency, drives the herbicidal activity of FM ‐1688, a novel PPO inhibitor

BACKGROUND The persistent challenge of weed competition in agriculture necessitates the development of novel herbicides with enhanced efficacy and improved physicochemical properties. This study employed a molecular hybridization strategy to optimize tiafenacil by incorporating cyclopropyl and cyclobutyl moieties into pyrimidinedione scaffolds, aiming to discover more effective protoporphyrinogen oxidase (PPO)‐inhibiting herbicides. RESULTS Thirty‐four novel pyrimidinedione derivatives were synthesized and evaluated for post‐emergence herbicidal activity. Structure–activity relationship (SAR) analysis revealed that cyclopropyl derivatives consistently outperformed cyclobutyl analogs, with methyl esters providing optimal activity. In the greenhouse assay, compound FM‐1688 ( 6aa ) demonstrated exceptional in vivo herbicidal efficacy, achieving 100% control of broadleaf weeds ( Zinnia elegans and Abutilon theophrasti ) at 2.34375 g active ingredient (a.i.)/ha and 80% control of grass weeds ( Echinochloa crus‐galli ) at 9.375 g a.i./ha, significantly surpassing the commercial standard tiafenacil (which achieved only 40% control of E. crus‐galli at the same rate). Crucially, enzymatic inhibition experiments revealed that FM‐1688 (half‐maximal inhibitory concentration (IC 50 ) = 5.95 n m ) possesses only minimally greater in vitro target‐site potency than tiafenacil (IC 50 = 6.85 n m ). This major discrepancy between in vivo efficacy and in vitro potency suggests the ‘cyclopropyl‐enhanced activity’ is not a target‐site (pharmacodynamic) effect. Molecular modeling supported this; docking studies revealed nearly identical binding poses and comparable binding energies (−8.6 kcal/mol for FM‐1688 versus −8.7 kcal/mol for tiafenacil). Instead, density functional theory (DFT) calculations identified the true driver: FM‐1688 possesses a significantly reduced molecular dipole moment (3.19 D) compared to tiafenacil (5.89 D), suggesting its superior greenhouse efficacy is driven by enhanced bioavailability and membrane permeability. CONCLUSION The cyclopropyl‐containing pyrimidinedione derivative FM‐1688 represents a highly promising herbicide candidate. Its superior in vivo activity appears to be driven by cyclopropyl‐enhanced pharmacokinetic properties (bioavailability) rather than enhanced target‐site binding. This finding provides a new rationale for agrochemical design, warranting further development for sustainable weed management.